The overall goal of this work is to define the neural mechanisms through which gastrointestinal hormones, especially cholecystokinin (CCK) and glucagon-related peptide (CCK), control food intake and to appreciate how these substrates are involved in the physiology and pathology of food intake and body weight. CCK is a peptide hormone secreted by enteroendcrine I cells of the upper small intestine, while GLP-1 is secreted by the L-cells of the distal jejunum, ileum and colon. Evidence from our lab and others suggests that while CCK and GLP-1 both alter short-term food intake, they also may influence the long-term control of food intake and body weight by interacting with other signals, such as fat cell hormone, leptin. The neural substrates through which CCK and GLP-1 interact with leptin to influence long-term control of food intake and body weight are not understood. Furthermore, it is not known whether hormones like CCK and GLP-1 activate the same or distinct peripheral neural substrates. Finally, while nearly all investigations of CCK's involvement in control of food intake have used the C-terminal 8 amino acid CCK fragment, CCK-8, CCK-8 is not a physiological form of circulating CCK in the rat. Rather, it is now clear that the 58 amino acid form of CCK, CCK-58, is the only circulating form of CCK. Because physiological responses to CCK-58 differ both quantitatively and qualitatively from responses to CCK-8, it now is important to specifically evaluate CCK-58's effect on feeding and body weight control, as well as CCK-58's ability to interact with leptin in control of food intake and body weight. The experiments proposed in this application will 1) characterize the effects of CCK-58, alone and in combination with leptin, on the activation of vagal afferents in culture and on meal parameters and body weight gain of rats, 2) use surgical and neurotoxin-induced vagal afferent destruction to determine the role of vagal afferents in control of 24h food intake by CCK and leptin and 3) use retrograde neuronal labeling, ratiometric calcium imaging, and near arterial infusions to determine the relative distribution of GLP-1 and CCK responsiveness of vagal afferents innervating the jejuno-ileum, duodenum and stomach, and to determine whether leptin modulates activation of vagal afferents and control of food intake by GLP-1. The results of these experiments will expand our understanding, specifically with regard to the role of visceral afferents in cooperative control of food intake and body weight by enteroendocrine signals and leptin. The substrates of such cooperative control are likely to be critical components in the control of food intake and body weight during health and disease. PUBLIC HEALTH RELEVANCE: This research is intended to characterize the interaction of gastrointestinal hormones with other signals, such as leptin, and to determine the extent to which visceral afferents participate in the cooperative control of food intake and body weight by gastrointestinal hormones and leptin.